The pathogenesis of diabetic nephropathy (DN) is not well understood but circumstantial evidence indicates a genetic basis. Microalbuminuria and macroalbuminuria/proteinuria are important markers of DN and predict renal progression and risk of cardiovascular morbidity and mortality. Urinary albumin excretion, measured as albumin to creatinine ratio (ACR), has been shown to be heritable in our preliminary analysis of urine data on 405 participants of San Antonio Family Diabetes Study (SAFADS), initially recruited on the basis of type 2 diabetic proband. Preliminary multipoint linkage analysis for albuminuria involving 335 genotyped individuals using urine albumin to urine creatinine ratio equal to or > .03 as a discrete trait showed strong evidence of linkage to a genetic location near marker GABRB3 on chromosome 15 (LOD = 3.3). The gene for tight junction protein-1 (TJP-1) has been mapped to a chromosomal region very close to the linkage signal identified. TJP-1 is a peripheral membrane-associated protein that is believed to play a central role in organizing the highly modified tight junction known as slit diaphragm of the glomerular epithelial cells. We have phenotyped approximately a total of 700 individuals from the 39 families enrolled in SAFADS. We will extend genotyping and analysis to all participants whose phenotypic data for DN are now available but who have not yet been genotyped (300 individuals), in order to confirm susceptibility loci for albuminuria by increasing the power of the linkage analysis. We will investigate positional candidate genes(s) influencing susceptibility to albuminuria, by identifying DNA sequence variants that are responsible for the linkage signal. We will focus on our selected candidate gene, TJP-1, by first identifying variants (single nucleotide polymorphisms - SNPs) within the upstream promoter region, 5' and 3' untranslated regions (UTR), exons, and splice sites of the TJP-1 gene that are present in our Mexican-American SAFADS population by direct sequencing. For each variant identified, we will genotype all 700 individuals. We will conduct a conditional linkage/linkage disequilibrium analysis to determine whether one or more SNPs are responsible for the linkage signal. Variants of this gene that impair its proper function could, hence, lead to increased glomerular capillary permeability and albuminuria.